IX. Should Selection of an Empiric Antibiotic Regimen for VAP Be Guided by Local Antibiotic-Resistance Data?

Recommendations

1. We recommend that all hospitals regularly generate and disseminate a local antibiogram, ideally one that is specific to their intensive care population(s) if possible.

2. We recommend that empiric treatment regimens be informed by the local distribution of pathogens associated with VAP and their antimicrobial susceptibilities. Values and preferences: These recommendations place a high value on targeting the specific pathogens associated with VAP as narrowly as possible to assure adequate treatment while minimizing overtreatment and its undesirable consequences.

Remarks: The frequency with which the distribution of pathogens and their antimicrobial susceptibilities are updated should be determined by the institution. Considerations should include their rate of change, resources, and the amount of data available for analysis.

X. What Antibiotics Are Recommended for Empiric Treatment of Clinically Suspected VAP?

Recommendations

1. In patients with suspected VAP, we recommend including coverage for S. aureus, Pseudomonas aeruginosa, and other gram-negative bacilli in all empiric regimens (strong recommendation, low-quality evidence).

i. We suggest including an agent active against MRSA for the empiric treatment of suspected VAP only in patients with any of the following: a risk factor for antimicrobial resistance, patients being treated in units where >10%–20% of S. aureus isolates are methicillin resistant, and patients in units where the prevalence of MRSA is not known (weak recommendation, very low-quality evidence).

ii. We suggest including an agent active against methicillin- sensitive S. aureus (MSSA) (and not MRSA) for the empiric treatment of suspected VAP in patients without risk factors for antimicrobial resistance, who are being treated in ICUs where <10%–20% of S. aureus isolates are methicillin resistant (weak recommendation, very low-quality evidence).

2. If empiric coverage for MRSA is indicated, we recommend either vancomycin or linezolid (strong recommendation, moderate-quality evidence).

3. When empiric treatment that includes coverage for MSSA (and not MRSA) is indicated, we suggest a regimen including piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem (weak recommendation, very low-quality evi- dence).

Oxacillin, nafcillin, or cefazolin are preferred agents for treatment of proven MSSA, but are not necessary for the empiric treatment of VAP if one of the above agents is used.

4. We suggest prescribing 2 antipseudomonal antibiotics from different classes for the empiric treatment of suspected VAP only in patients with any of the following: a risk factor for

antimicrobial resistance, patients in units where >10% of gram-negative isolates are resistant to an agent being considered for monotherapy, and patients in an ICU where local antimicrobial susceptibility rates are not available (weak recommendation, low-quality evidence).

5. We suggest prescribing one antibiotic active against P. aeruginosa for the empiric treatment of suspected VAP in patients without risk factors for antimicrobial resistance who are being treated in ICUs where ≤10% of gram-negative isolates are resistant to the agent being considered for monotherapy (weak recommendation, low-quality evidence).

6. In patients with suspected VAP, we suggest avoiding aminoglycosides if alternative agents with adequate gram-negative activity are available (weak recommendation, low-quality evidence).

7. In patients with suspected VAP, we suggest avoiding colistin if alternative agents with adequate gram-negative activity are available (weak recommendation, very low-quality evidence). Values and Preferences: These recommendations are a compromise between the competing goals of providing early appropriate antibiotic coverage and avoiding superfluous treatment that may lead to adverse drug effects, Clostridium difficile infections, antibiotic resistance, and increased cost.

Remarks: Risk factors for antimicrobial resistance are provided in Table 2. The 10%–20% threshold for deciding whether or not to target MRSA and the 10% threshold for deciding whether or not to prescribe 1 antipseudomonal agent or 2 were chosen by the panel with a goal of trying to assure that ≥95% of patient receive empiric therapy ac- tive against their likely pathogens; when implementing these recommendations, individual ICUs may elect to mod- ify these thresholds. If patient has structural lung disease increasing the risk of gram-negative infection (ie, bronchiectasis or cystic fibrosis), 2 antipseudomonal agents are recommended.

XI. Should Selection of an Empiric Antibiotic Regimen for HAP (Non-VAP) Be Guided by Local Antibiotic Resistance Data?

Recommendations

1. We recommend that all hospitals regularly generate and disseminate a local antibiogram, ideally one that is tailored to their HAP population, if possible.

2. We recommend that empiric antibiotic regimens be based upon the local distribution of pathogens associated with HAP and their antimicrobial susceptibilities.

Remarks: The frequency with which the distribution of pathogens and their antimicrobial susceptibilities are updated should be determined by the institution. Considerations should include their rate of change, resources, and the amount of data available for analysis.

XII. What Antibiotics Are Recommended for Empiric Treatment of Clinically Suspected HAP (Non-VAP)?

i. For patients with HAP who are being treated empirically and have either a risk factor for MRSA infection (ie, prior intravenous antibiotic use within 90 days, hospitalization in a unit where >20% of S. aureus isolates are meth- icillin resistant, or the prevalence of MRSA is not known, or who are at high risk for mortality, we suggest prescribing an antibiotic with activity against MRSA (weak recommenda- tion, very low-quality evidence). (Risk factors for mortality include need for ventilatory support due to HAP and septic shock).

ii. For patients with HAP who require empiric coverage for MRSA, we recommend vancomycin or linezolid rather than an alternative antibiotic (strong recommendation, low-quality evidence).

iii. For patients with HAP who are being treated empirically and have no risk factors for MRSA infection and are not at high risk of mortality, we suggest prescribing an antibiotic with activity against MSSA. When empiric treatment that includes coverage for MSSA (and not MRSA) is indicated, we suggest a regimen including piperacillin-tazobactam, cefepime, levofloxacin, imipenem, or meropenem. Oxacillin, nafcillin, or cefazolin are preferred for the treatment of proven MSSA, but are not necessary for empiric coverage of HAP if one of the above agents is used (weak recommendation, very low-quality evidence).

2. For patients with HAP who are being treated empirically, we recommend prescribing antibiotics with activity against P. aeruginosa and other gram-negative bacilli (strong recommendation, very low-quality evidence).

i. For patients with HAP who are being treated empirically and have factors increasing the likelihood for Pseudomonas or other gram-negative infection (ie, prior intravenous antibiotic use within 90 days; also see Remarks) or a high risk for mortality, we suggest prescribing antibiotics from 2 different classes with activity against P. aeruginosa (weak recommendation, very low-quality evidence).

(Risk factors for mortality include need for ventilatory support due to HAP and septic shock). All other patients with HAP who are being treated empirically may be prescribed a single antibiotic with activity against P. aeruginosa.

ii. For patients with HAP who are being treated empirically, we recommend not using an aminoglycoside as the sole antipseudomonal agent (strong recommendation, very low-quality evidence).

Values and Preferences: These recommendations are a compromise between the competing goals of providing early appropriate antibiotic coverage and avoiding super- fluous treatment that may lead to adverse drug effects, C. difficile infections, antibiotic resistance, and increased cost.

Remarks: The 20% threshold for deciding whether or not to target MRSA or MSSA was chosen in an effort to balance the need for effective initial antibiotic therapy against the risks of excessive antibiotic use; when implementing these recommendations, individual units may elect to modify this thresh- old. If patient has structural lung disease increasing the risk of gram-negative infection (ie, bronchiectasis or cystic fibrosis), 2 antipseudomonal agents are recommended. A high-quality Gram stain from a respiratory specimen with numerous and predominant gram-negative bacilli provides further support for the diagnosis of a gram-negative pneumonia, including fermenting and non-glucose-fermenting microorganisms.

PHARMACOKINETIC/PHARMACODYNAMIC OPTIMIZATION OF ANTIBIOTIC THERAPY

XIII. Should Antibiotic Dosing Be Determined by Pharmacokinetic/ Pharmacodynamic (PK/PD) Data or the Manufacturer’s Prescribing Information in Patients With HAP/VAP?

Recommendation

1. For patients with HAP/VAP, we suggest that antibiotic dosing be determined using PK/PD data, rather than the manufacturer’s prescribing information (weak recommendation, very low-quality evidence).

Values and Preferences: This recommendation places a high value on improving clinical outcome by optimization of therapy; it places a lower value on burden and cost.

Remarks: PK/PD-optimized dosing refers to the use of antibiotic blood concentrations, extended and continuous infusions, and weight-based dosing for certain antibiotics.

ROLE OF INHALED ANTIBIOTIC THERAPY

XIV. Should Patients With VAP Due to Gram-Negative Bacilli Be Treated With a Combination of Inhaled and Systemic Antibiotics, or Systemic Antibiotics Alone?

Recommendation

1. For patients with VAP due to gram-negative bacilli that are susceptible to only aminoglycosides or polymyxins (colistin or polymyxin B), we suggest both inhaled and systemic antibiotics, rather than systemic antibiotics alone (weak recommendation, very low-quality evidence).

Values and Preferences: This recommendation places a high value on achieving clinical cure and survival; it places a lower value on burden and cost.

Remarks: It is reasonable to consider adjunctive inhaled anti- biotic therapy as a treatment of last resort for patients who are not responding to intravenous antibiotics alone, whether the infecting organism is or is not multidrug resistant (MDR).

PATHOGEN-SPECIFIC THERAPY

XV. What Antibiotics Should Be Used for the Treatment for MRSA HAP/VAP?

Recommendation

1. We recommend that MRSA HAP/VAP be treated with either vancomycin or linezolid rather than other antibiotics or antibiotic combinations (strong recommendation, moder- ate-quality evidence).

Remarks: The choice between vancomycin and linezolid may be guided by patient-specific factors such as blood cell counts, concurrent prescriptions for serotonin-reuptake inhibitors, renal function, and cost.

XVI. Which Antibiotic Should Be Used to Treat Patients With HAP/VAP Due to P. aeruginosa?

Recommendations

1. For patients with HAP/VAP due to P. aeruginosa, we recommend that the choice of an antibiotic for definitive (not empiric) therapy be based upon the results of antimicrobial susceptibility testing (strong recommendation, low-quality evidence).

2. For patients with HAP/VAP due to P. aeruginosa, we recommend againstaminoglycoside monotherapy (strong recom- mendation, very low-quality evidence).

XVII. Should Monotherapy or Combination Therapy Be Used to Treat Patients With HAP/VAP Due to P. aeruginosa?

Recommendations

1. For patients with HAP/VAP due to P. aeruginosa who are not in septic shock or at a high risk for death, and for whom the results of antibiotic susceptibility testing are known, we recommend monotherapy using an antibiotic to which the isolate is susceptible rather than combination therapy (strong recommendation, low-quality evidence).

2. For patients with HAP/VAP due to P. aeruginosa who remain in septic shock or at a high risk for death when the results of antibiotic susceptibility testing are known, we suggest combination therapy using 2 antibiotics to which the isolate is susceptible rather than monotherapy (weak recommenda- tion, very low-quality evidence).

3. For patients with HAP/VAP due to P. aeruginosa, we recommend against aminoglycoside monotherapy (strong recommendation, very low-quality evidence).

Remarks: High risk of death in the meta-regression analysis was defined as mortality risk >25%; low risk of death is defined as mortality risk <15%. For a patient whose septic shock resolves when antimicrobial sensitivities are known, continued combination therapy is not recommended.

XVIII. Which Antibiotic Should Be Used to Treat Patients With HAP/VAP Due to Extended-Spectrum β-Lactamase (ESBL)–Producing Gram- Negative Bacilli?

Recommendation

1. For patients with HAP/VAP due to ESBL-producing gram- negative bacilli, we recommend that the choice of an antibiotic for definitive (not empiric) therapy be based upon the results of antimicrobial susceptibility testing and patient-specific factors (strong recommendation, very low-quality evidence).

Remarks: Patient-specific factors that should be considered when selecting an antimicrobial agent include allergies and comorbidities that may confer an increased risk of side effects.

XIX. Which Antibiotic Should Be Used to Treat Patients With HAP/VAP Due to Acinetobacter Species?

Recommendations

1. In patients with HAP/VAP caused by Acinetobacter species, we suggest treatment with either a carbapenem or ampicillin/ sulbactam if the isolate is susceptible to these agents (weak recommendation, low-quality evidence).

2. In patients with HAP/VAP caused by Acinetobacter species that is sensitive only to polymyxins, we recommend intravenous polymyxin (colistin or polymyxin B) (strong recommendation, low-quality evidence), and we suggest adjunctive inhaled colistin (weak recommendation, low-quality evidence).

3. In patients with HAP/VAP caused by Acinetobacter species that is sensitive only to colistin, we suggest not using adjunc- tive rifampicin (weak recommendation, moderate-quality evidence).

4. In patients with HAP/VAP caused by Acinetobacter species, we recommend against the use of tigecycline (strong recommendation, low-quality evidence).

Values and Preferences: These recommendations place a rela- tively higher value on avoiding potential adverse effects due to the use of combination therapy with rifampicin and colistin, over achieving an increased microbial eradication rate, as eradication rate was not associated with improved clinical outcome.

XX. Which Antibiotic Should Be Used to Treat Patients With HAP/VAP Due to Carbapenem-Resistant Pathogens?

Recommendation

1. In patients with HAP/VAP caused by a carbapenem-resistant pathogen that is sensitive only to polymyxins, we recommend intravenous polymyxins (colistin or polymyxin B) (strong recommendation, moderate-quality evidence), and we suggest adjunctive inhaled colistin (weak recommendation, low-quality evidence).

Values and Preferences: These recommendations place a high value on achieving clinical cure and survival; they place a lower value on burden and cost.

Remarks: Inhaled colistin may have potential pharmacokinetic advantages compared to inhaled polymyxin B, and clinical evidence based on controlled studies has also shown that inhaled colistin may be associated with improved clinical outcomes. The clinical evidence for inhaled polymyxin B is mostly from anecdotal and uncontrolled studies; we are therefore not suggesting use of inhaled polymyxin B. Colistin for inhalation should be administered promptly after being mixed with sterile water. This recommendation was made by the US Food and Drug Administration (FDA) after a report that a cystic fibrosis patient died after being treated with a premixed colistin formulation. Intravenous polymyxin B may have potential pharmacokinetic advantages compared to intravenous colistin, but clinical data are lacking in patients with HAP/VAP.

LENGTH OF THERAPY

XXI. Should Patients With VAP Receive 7 Days or 8–15 Days of Antibiotic Therapy?

Recommendation

1. For patients with VAP, we recommend a 7-day course of antimicrobial therapy rather than a longer duration (strong recommendation, moderate-quality evidence).

Remarks: There exist situations in which a shorter or longer duration of antibiotics may be indicated, depending upon the rate of improvement of clinical, radiologic, and laboratory parameters.

XXII. What Is the Optimal Duration of Antibiotic Therapy for HAP (Non-VAP)?

Recommendation

1. For patients with HAP, we recommend a 7-day course of antimicrobial therapy (strong recommendation, very low- quality evidence).

Remarks: There exist situations in which a shorter or longer duration of antibiotics may be indicated, depending upon the rate of improvement of clinical, radiologic, and laboratory parameters.

XXIII. Should Antibiotic Therapy Be De-escalated or Fixed in Patients With HAP/VAP?

Recommendation

1. For patients with HAP/VAP, we suggest that antibiotic therapy be de-escalated rather than fixed (weak recommendation, very low-quality evidence).

Remarks: De-escalation refers to changing an empiric broad-spectrum antibiotic regimen to a narrower antibiotic regimen by changing the antimicrobial agent or changing from combination therapy to monotherapy. In contrast, fixed antibiotic therapy refers to maintaining a broad-spectrum antibiotic regimen until therapy is completed.

XXIV. Should Discontinuation of Antibiotic Therapy Be Based Upon PCT Levels Plus Clinical Criteria or Clinical Criteria Alone in Patients With HAP/VAP?

Recommendation

1. For patients with HAP/VAP, we suggest using PCT levels plus clinical criteria to guide the discontinuation of antibiotic therapy, rather than clinical criteria alone (weak recommendation, low-quality evidence).

Remarks: It is not known if the benefits of using PCT levels to determine whether or not to discontinue antibiotic therapy exist in settings where standard antimicrobial therapy for VAP is already 7 days or less.

XXV. Should Discontinuation of Antibiotic Therapy Be Based Upon the CPIS Plus Clinical Criteria or Clinical Criteria Alone in Patients With Suspected HAP/VAP?

Recommendation

1. For patients with suspected HAP/VAP, we suggest not using the CPIS to guide the discontinuation of antibiotic therapy (weak recommendation, low-quality evidence).